Application of Hard-Soft Acid-Base (HSAB) Theory to Reactions - PowerPoint PPT Presentation

Application of Hard-Soft Acid-Base (HSAB) Theory to Reactions between Amino Acids and Quinone Methides Samuel Edeh Edeh Samuel - Faculty mentor Faculty mentor – – Dr. Robert Dyer Dr. Robert Dyer - 2004 Student Research Conference 2004 Student Research Conference Truman State University, Kirksville MO Truman State University, Kirksville MO

Introduction: Introduction: � Bronsted Bronsted Acid/Base Concept Acid/Base Concept � – Acid donates H Acid donates H + – + – Base accepts H Base accepts H + + – � Lewis Acid/Base Concept Lewis Acid/Base Concept � – Acid accepts electrons (e Acid accepts electrons (e - - ) ) – – Base donates electrons (e Base donates electrons (e - ) – - )

Introduction: Introduction: � Hard Hard- -Soft Acid Soft Acid- -Base (HSAB) Theory Base (HSAB) Theory � – Ralph G. Pearson (1963) Ralph G. Pearson (1963) – – “Hard acids prefer to associate with hard “Hard acids prefer to associate with hard – bases, and soft acids prefer to associate bases, and soft acids prefer to associate with soft bases.” with soft bases.”

Background: Background: � Molecular Molecular orbitals orbitals � – Highest Occupied Molecular Orbital, HOMO Highest Occupied Molecular Orbital, HOMO – – Lowest Unoccupied Molecular Orbital, LUMO Lowest Unoccupied Molecular Orbital, LUMO – Unocccupied E n+2 ( + ) Molecular LUMO E n+1 Orbitals ↑↓ HOMO E n Occcupied ↑↓ E 3 ( - ) Molecular Orbitals ↑↓ E 2 ↑↓ E 1

Background: Background: � Electron affinity, Electron affinity, A A � – Energy change when atom accepts an Energy change when atom accepts an – electron electron – Energy of LUMO ( Energy of LUMO (- -) ) – E n+2 LUMO E n+1 ↑↓ HOMO E n ↑↓ E 3 ↑↓ E 2 ↑↓ E 1

Background: Background: � Ionization energy, Ionization energy, I I � – Energy required to remove an electron Energy required to remove an electron – from an atom from an atom – Energy of HOMO (+) Energy of HOMO (+) – E n+2 LUMO E n+1 ↑↓ HOMO E n ↑↓ E 3 ↑↓ E 2 ↑↓ E 1

Background: Background: η Absolute hardness, η � Absolute hardness, � I − A η = 2 HOMO − LUMO η = 2 http://web.utk.edu/ ~ cebarnes/C430/lecs/weblec6.pdf η = − 2 HOMO LUMO

Background: Background: σ Absolute softness, σ � Absolute softness, � σ = 1 η � Reactivity Reactivity � – “Hard acids prefer to associate with hard “Hard acids prefer to associate with hard – bases, and soft acids prefer to associate bases, and soft acids prefer to associate with soft bases.” with soft bases.”

Method: Method: � Calculate Calculate � – LUMO and HOMO energies LUMO and HOMO energies – – η η – � Predict reactivity Predict reactivity � η ) (Based on η ) (Based on � Computer program Gaussian Computer program Gaussian �

Experiment: Experiment: O O H 2 N CH C OH (H 3 C) 3 C C(CH 3 ) 3 CH 2 + CH 2 CH 2 CH 2 NH 2 tert - -ButylMethyl ButylMethyl tert Arginine Arginine Quinone Methide Methide Quinone ( t t - -BMQM) BMQM) (

Computation: Computation: � tert tert - -ButylMethyl ButylMethyl Quinone Quinone Methide Methide ( ( t t - -BMQM) BMQM) � – Electrophile Electrophile (accepts electrons into LUMO) (accepts electrons into LUMO) – – HF 3 HF 3- -21G* 21G* – – HF 6 HF 6- -311G 311G – � Amino acids Amino acids � – Nucleophiles Nucleophiles (donate electrons from HOMO) (donate electrons from HOMO) – – HF 3 HF 3- -21G* 21G* – – HF 6 HF 6- -311G 311G –

Geometry optimization Geometry optimization HF 3 - 21G* |2 η | HOMO LUMO t -BMQM -0.32053 0.05119 0.37172 Arginine -0.34805 0.19350 0.54155 Isoleucine -0.36465 0.18352 0.54817 Tryptophan -0.28232 0.13472 0.41704 Cysteine -0.36193 0.12653 0.48846 Lysine -0.36129 0.18477 0.54606 Tyrosine -0.31102 0.13958 0.45060

Geometry optimization Geometry optimization HF 6 - 311G |2 η | HOMO LUMO t -BMQM -0.3185 0.04561 0.36414 Arginine -0.3309 0.13512 0.46603 Isoleucine -0.3744 0.14242 0.51681 Tryptophan -0.2866 0.11992 0.40649 Cysteine -0.3659 0.12568 0.49154 Lysine -0.3714 0.14950 0.52090 Tyrosine -0.3164 0.12339 0.43977

Result analysis: Result analysis: Relative rates for reaction between t -BMQM and Relative rates for reaction between amino acids k ( M -1 s -1 ) † HF 3-21G* HF 6-11G Cys 3320 Tryp Tryp Tyr 45.0 Tyr Tyr Arg 17.2 Cys Arg Tryp 14.1 Arg Cys Ile 7.90 Ile Ile † J. Org. Chem. 1997 , 62 , 1820-1825

Why is data discrepant with Why is data discrepant with published relativities? published relativities? � Used fairly simple Gaussian computation Used fairly simple Gaussian computation � � Ignored nature of reaction system Ignored nature of reaction system � -pH pH - -Temperature Temperature - -Solvent Solvent - � Optimization level Optimization level �

Why study quinone quinone methides methides? ? Why study � Good guy: Good guy: � -Melanization Melanization - -Sclerotization Sclerotization - -Lignin formation Lignin formation - � Bad guy: Bad guy: � -Cytotoxicity Cytotoxicity -

Acknowledgments Acknowledgments Thanks to Thanks to – Dr. Robert G. Dyer Dr. Robert G. Dyer – – You for listening You for listening – Questions? Questions? ftÅâxÄ Xwx{ ftÅâxÄ Xwx{